We have previously demonstrated that bacterial lipopolysaccharide (LPS) is capable of promoting Coxsackie B3 (CB3)-induced myocarditis in genetically resistant B10.A mice. Because LPS is known to increase production of various cytokines, we tested CB3-infected, LPS-treated mice for the presence of interleukin 1 (IL-1) and tumor necrosis factor (TNF). We found significantly increased amounts of both cytokines in the sera of CB3/LPS-treated mice compared with animals treated only with LPS. We also found immunohistochemical evidence for local production of these cytokines in the cardiac tissue of CB3/LPS-treated mice. Treatment with IL-1 or TNF alone promoted CB3-induced autoimmune myocarditis in resistant B10.A mice. Myocarditis was also observed when uninfected mice were immunized with syngeneic heart extract in the presence of IL-1 or TNF.